| As one of the main cancer therapeutic methods, chemotherapy plays a vital role in clinical practice. However, the conditional chemotherapy drugs and the dosage regimens have lots of limits, such as narrow therapeutic window, lower stability, toxicity, and lack of targeting, due to the metabolism barriers and the physical and chemical properties of these drugs. In addition, the molecule mechanism of tumor formation is complex and various, so drug resistance must be led to. Therefore, there are apparente limitations with single drug for chemotherapy. Combination of multi-drug for chemotherapy has been a consideration strategy in cancer therapy, and the sequential controlled release of multiple drugs could minimize the toxicity, enhance synergy and maximize the efficacy of treatment. It has significant value for chemotherapy of cancer and clinical treatment of other complex diseases (e.g. malaria, AIDS).Based on the aforemationed, a novel drug delivery system—micro/ nanoparticles with core-shell structures has been constructed in this paper. Except for encapsulating two model drugs, rhodamine B (hydrophilicity) and naproxen (hydrophobicity), the system could also achieve sequential and distinct drug release through regulating the loading positions of the drugs. With the merit of micro/nanoparticles that could easily be made into different dosage forms, the system provides a new strategy and good alternative for programmable controlled release of multi-drug delivery in combination chemotherapy of cancer and other complex diseases. The main research work and corresponding results were done in this thesis.①Rhodamine B-/naproxen-chitosan nanoparticles were prepared by ionic gelation method. Orthogonal experiment displayed that the optimistic conditions were as follows: the concentration of CS was 2.0mg/mL, TPP 0.8mg/mL, drug 0.2mg/mL and pH4.5. The morphology of nanoaprticles was roughly spherical and distributed uniformly. The average size and zata potential of rhodamine B-CS nanoparticles were 402±23nm and +4.52±0.31mV. The encapsulation efficacy and drug loading capacity were 54.07±2.74% and 2.87±0.86%, respectively. The average size of naproxen-CS nanoparticles was 557±37nm, and zata potential was +4.26±0.13mV. The encapsulation efficacy and drug loading capacity were 26.47±0.19% and 1.53±0.21%, respectively. The release behaviors were more close to Higuchi equation, which indicated the drug release from nanoparticles was mainly controlled by diffusion mechanism. While in the last stage of release, the R value was smaller, which suggested the drug release process became to follow a first-order kinetic model, depicting sustained drug release from nanoparticles.②Drug-loaded micro/nanoparticles were fabricated by electrospraying with the matrix of polyvinylpyrrolidone and a model drug of naproxen. The results indicated that morphology of the particles and the drug release were impacted by the PVP concentration. When the concentration decreased, the particles became adhesive, and the average size diminished from 1.6μm (18wt%) down to 580.2nm (8wt%). In vitro release demonstrated it depended on diffusion with a high PVP concentration (Higuchi equation: R=0.9874). It could be guessed that naproxen was released through the swelling and dissolving of PVP, and displayed obviously sustained release. When the polymer concentration was low, the release was more close to the first-order model (R=0.9807), suggesting the release process depended on the dissolving of PVP.③Dual-wavelength spectrophotometry was established to directly detect the concentration of rodamine B and naproxen at the same time. The calibration curve of rhodamine B was created at 554nm. Naproxen showed a characteristic peak at 330nm and its reference wavelength was 369 nm. The average recovery rate of rhodamine B was 99.92±0.75%, RSD was 0.75%, and the correlation coefficient was 0.9999. The three data of naproxen were 99.99±0.35%, 0.35%, and 0.9999, respectively.④Based on the above, core-shell micro/nanoparticles were successfully fabricated by electrospraying, with rhodamine B and naproxen as the model drugs. After dual-labled, images of FM demonstrated the core-shell structure, with CS-nanoparticles as the core and PVP as the shell. Drug release profiles described that naproxen released faster than rhodamine B when the former was located in the shell and the latter was located in the core. The 72h accumulated release rates were 92.9±3.5% and 39.0±1.3%, respectively. On the contrary, rhodamine B released faster than naproxen and their 72h accumulated release rates were 97.8±4.0% (rhodamine B) and 85.1±4.2% (naproxen), respectively. Therefore, the differences of polymer properties and drugs distribution in carriers could result in the distinct release behaviors of dual drugs encapsulated. Programmable controlled release couled be achieved through adjusting the composition matrix and the distribution position of the drugs.
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